Drug induced Pathological Gambling

Poster Presentations Assessment of comorbidities in patients with Symptomatic Knee osteoarthritis in Spain: the emartro study S. Giménez Basallote1; J. Vergara Martín2; J.L. Llisterri Caro3; G. Rodríguez Roca4; J. Monfort Faure5; F.J. de Abajo Iglesias6; J. Ríos Guillermo7; L. Sánchez Bellmunt8; M. Herrero Barbero8; and J. Vergés Milano8 1 Centro de Salud Limonar, Málaga, Spain; 2Centro de Salud Huércal de Almería, Almería, Spain; 3Centro de Salud Ingeniero Joaquín Benlloch, Valencia, Spain; 4Centro de Salud de la Puebla de Montalbán, Toledo, Spain; 5Hospital del Mar, Barcelona, Spain; 6 Hospital Universitario Príncipe de Asturias, Madrid, Spain; 7 IDIBAPS, Hospital Clínic Barcelona, Barcelona, Spain; and 8 Bioibérica, S.A., Barcelona, Spain Introduction:  The primary outcome of the study is to assess the prevalence of comorbidities in symptomatic knee osteoarthritis (KOA) patients. Additionally, potential differentiating factors between KOA and non-osteoarthritic subjects will be assessed to detect a possible prognosis effect complementary to osteoarthritis. Here we present the protocol of the study that is being conducted at the moment. Material and Methods:  It’s an observational, epidemiologic, multicenter, transversal study comparing comorbidities between subjects with and without KOA. The recruitment will be carried out by 65 investigators from different Spanish’s healthcare centers. 1150 subjects will be enrolled distributed in two groups: 575 KOA subjects selected and 575 sex and age-matched control subjects, without neither knee pain nor osteoarthritis. The results will be analyzed using descriptive statistics. Results:  This study will provide new information about comorbidities in osteoarthritis which has become the leading cause of disability in the elderly and permanent disability caused by a rheumatic disease (RD) and one of the most frequent reasons for consultation. In other studies, it has been observed that the prevalence of comorbidities was significantly higher in osteoarthritis patients than controls (P <  0.0001) being hypertension, diabetes mellitus, chronic obstructive pulmonary disease, stroke and myocardial infarction the most prevalent osteoarthritis comorbidities. The ongoing study is in the follow-up period. Conclusions: Osteoarthritis is the most common RD, affecting 28% of those over 60 years, enduring pain, functional disability, decreased quality of life and causing significant social and economic burden. However, an important proportion of the economical costs of osteoarthritis compared to non-osteoarthritic population is due to an excessive use of sanitary resources which includes not only pharmacological treatment but also image and laboratory tests, management of treatment adverse reactions or rehabilitation and surgical interventions. The knowledge of comorbidities and concomitant medications in KOA patients will provide useful information to manage the disease more effectively and reduce its social and economic burden.

Valproic Acid and Carbapenems interaction: clinical outcomes A.L. Arellano1,2; A. Barriocanal2,3; Y. Sanz1; and E. Montané1,2 Hospital Universitari Germans Trias i Pujol, Barcelona, Spain; 2 Universitat Autònoma de Barcelona, Spain; and 3Fundació d’Investigació en Ciències de la Salut Germans Trias i Pujol, Barcelona, Spain Background or Introduction:  One of the setbacks of the valproic acid (VPA) is the potential for pharmacological interactions. Although the decrease in the VPA serum concentrations in patients receiving

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carbapenems is well known, the available data are focused on pharmacokinetic studies rather than clinical implications. Objective: to evaluate the clinical outcome due to interaction between VPA and carbapenems. Material and Methods:  An observational, retrospective and unicentric study was performed. Patients whose VPA plasma levels were closely monitored by our department and that had been simultaneously treated with a carbapenem from 2011 to 2014 were included. Demographic variables, VPA plasma levels, changes in prescription, electroencephalogram (EEG), and seizures were analyzed. Results:  Of 66 patients with VPA plasmatic levels closely monitored, 9 (14%) had an interaction with a carbapenem. Of these nine, 56% (5) were female, with a median age of 47 years, range 18-76. All of the patients were hospitalized in the intensive care unit and received meropenem concomitantly to VPA. After the introduction of meropenem, the mean decrease of the VPA plasmatic levels was 29.3 mg/L, range from 5 to 48 mg/L. In four patients (44.4%) the meropenem was stopped, in three (33.3%) was switched to another antibiotic and in 2 (22.2%) was continued. All the patients required an increase of the VPA dosage. In three patients (33.3%) the drug interaction had clinical consequences (in one patient the VPA level dropped 40 mg/L causing a seizure, and in the other two their EEGs showed seizure activity without clinical convulsions, probably due to general sedation). Conclusions: A third of the patients treated concomitantly with VPA and meropenem had clinical implications such as seizures (one patient) and EEGs with seizure activity (two patients). Simultaneous administration of both drugs should be avoided when possible. If not, VPA plasmatic levels should be closely monitored.

Drug induced Pathological Gambling P. Figueroa1; N. García Doladé2; and G. Cereza2 1 Clinical Pharmacology Service. Vall d’Hebron Hospital, Barcelona, Spain; and 2Fundació Institut Català de Farmacologia, Barcelona, Spain Introduction:  Pathological gambling is a severe impulse control disorder. It has been associated with dopaminergic drugs prescribed to treat Parkinson’s disease (PD). In recent years, it also has been reported cases with aripiprazole. We aimed to describe the main characteristics of spontaneous reports about pathological gambling received by the Spanish Pharmacovigilance System (SPvS). Material and Methods:  Spontaneous reports of PG received by the SPvS from 1983 to 2014 were selected. The variables analyzed were age and sex of the patients, suspect drugs and therapeutic indication, other concomitant adverse drug reactions (ADRs), severity and outcome, latency period, rechallenge, underlying conditions and alternative causes. Results: Until December 2014 the SPvS database had gathered 203,582 spontaneous reports of ADRs, 15 of them described pathological gambling. All cases were male with a median age of 60 years (46 to 84 years). The total number of suspect drugs was 24; all of them were dopaminergic agents, mainly dopamine agonists (15). The drug most frequently reported was pramipexole (10 cases) followed by and ropinirole (3). All patients were treated of PD. The latency period ranged from 1 month to 3 years. Besides pathological gambling, in three cases other ADRs were described; suicidal ideation (1 case), hypersexuality, dopamine dysregulation syndrome and drug abuse (1) and alcoholism (1). Thirteen reports were serious (86.6%); 6 patients improved after withdrawal of the suspect drug. Only one patient had history of previous gambling. Alternative explanations were excluded in 9 cases; there were no cases with a positive rechallenge.

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Clinical Therapeutics Conclusions: Drug-induced pathological gambling is a serious adverse reaction. Affected patients were treated for PD. Dopaminergic agents appear to be the only drugs involved, mainly pramipexole. Prescribing physicians should warn patients and their families in order to allow for early diagnosis of this condition, which would allow early intervention and thus avoid possible medical and social complications.

Brand-name to generic substitution of antiepileptic Drugs (AED) does not lead to seizure-related hospitalization: a Population-based case-crossover study E. Polard1; E. Nowak1; A. Happe1; A. Biraben2; and E. Oger1 Pharmacoepidemiology Team CTAD-PEPI, INSERM CIC-1414, Rennes University Hospital, France; and 2Neurology Department, Rennes University Hospital, France Introduction: There are still controversies over pill substitution among AEDs. We aimed at further estimating the association between generic substitution and loss of seizure control. Patients and Methods: We used data from the French National Health Insurance Information System linked with the French Hospital Discharge Database. We identified a cohort of adult patients who filled a prescription in 2009–2011 for AEDs that had at least one brand-name and one generic form available on the French market. Patients with a medical history of cancer and women who gave birth in 2009–2011 were excluded. We designed a case-crossover study; three months were used for the case- and the control-periods. The outcome date was defined as the date of first occurrence of hospitalization for seizure, code G40.x or G41.x, pending being G40/ G41 hospitalization-free period in the preceding year. We required individuals to have regular dispensations of AEDs within the year preceding the outcome date. Free patients were defined as patients who had only brand-name dispensations before the control period. B-G substitution was defined as a filled prescription for a generic AED that was preceded by a filled prescription for a brand-name counterpart. ORs and 95% CIs were estimated using conditional logistic regression model. Results:  A total of 8,379 patients (mean age ± SD, 52.7 ± 18.8 years; sex ratio male/female, 1.27) were analyzed. Discordant pairs were 491 with B-G substitution in the control period only and 478 with B-G substitution in the case period only; OR (95% CI) 0.97 (0.86– 1.10). No statistically significant interaction was detected among four pre-specified subgroup analyses (gender, age strata, free or nonfree patients and strict AED monotherapy or not). Controlling for non-seizure-related hospitalizations made no material difference. Sensitivity analyses yielded similar results. Conclusion:  B-G AED substitution was not associated with an elevated risk of seizure-related hospitalization. 1

The Mapk-activated protein Kinase 2 (MK2) inhibitor CMPD1 is a novel microtubule targeting agent for Glioblastoma Therapy F. Gurgis1; M. Åkerfeldt1; C. Wong2; B. Heng3; G.J. Guillemin3; M. Chircop2; and L. Munoz1 1 The University of Sydney, Sydney, Australia; 2Children’s Medical Research Institute, Sydney, Australia; and 3Macquarie University, Sydney, Australia Introduction:  Glioblastoma is among the most lethal and least successfully treated solid tumours. A suitable agent for brain tumour treatment must cross the blood-brain barrier and lack neurotoxicity.

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MAPK-activated protein kinase 2 (MK2) is a cell cycle checkpoint kinase involved in DNA damage response. MK2 inhibitors enhance efficacy of conventional chemotherapeutic agents, but their effectiveness as a single agent has not been investigated. Material and Methods:  The anti-cancer effectiveness of an MK2a substrate-selective p38 inhibitor CMPD1 (Boehringer-Ingelheim; Davidson et. al., Biochemistry 2004; 43(37):11658-71) was determined in a panel of glioblastoma cell lines and normal cells (primary human microglia, astrocytes and neurons) using cell viability, Annexin-V staining and cell cycle analysis. Immunofluorescence and tubulin polymerization assays were conducted to study the effect of CMPD1 on microtubules. Results:  The MK2 inhibitor CMPD1 demonstrated single agent anticancer efficacy with a submicro-molar IC50 in glioblastoma cells yet exhibited minimal toxicity on normal cells. Treatment of U87 cells with CMPD1 resulted in G2/M arrest and accumulation of a polyploid (> 4n) population. Moreover, CMPD1 induced apoptosis and affected the expression of anti-apoptotic proteins in glioblastoma cells. However, these observations were less evident in primary astrocytes. Interestingly, while reported to be MK2a substrate-selective p38 inhibitor, CMPD1 did not inhibit MK2 or its downstream target Hsp27 at doses that are cytotoxic in U87 cells. siRNA knockdown of MK2 did not alter the IC50 of CMPD1 suggesting that MK2 is not involved in cell death. Instead, we identified CMPD1 as a tubulin depolymerizing agent causing microtubule disruption in glioblastoma cells. Furthermore, we discovered that CMPD1 reduces the expression of tubulin in U87 cells and inhibited the self-renewal capacity of glioblastoma cells. Conclusions:  Collectively, we have discovered a novel microtubule targeting drug candidate with selective toxicity for glioblastoma therapy. We are currently developing analogues with enhanced bloodbrain barrier permeable properties.

Adverse events associated with ANTI-TNF therapy in inflammatory bowel disease cohort group in a Croatian Tertiary Centre V. Oršić  Frič1,2; S. Mimica-Matanović 1,2; and V. Borzan1,2 Clinical Hospital Centre Osijek, Osijek, Croatia; and 2Faculty of Medicine, Josip Juraj Strossmayer University of Osijek, Osijek, Croatia Introduction:  Biological therapy has significantly improved the treatment of patients with inflammatory bowel disease (IBD). Anti-Tumor Necrosis Factor (anti-TNF) agents infliximab (IFX) and adalimumab (ADA) are biologics most commonly used for the treatment of IBD, but with a burden of possible severe adverse events (AEs). Our objective was to present the evaluation of safety data on anti-TNF therapy in the cohort of IBD patients in our centre. Methods:  We included patients treated with anti-TNF therapy at the Department of Gastroenterology and Hepatology of Clinical Hospital Centre Osijek from 2005 to 2013. Data were collected from patient’s medical records and presented according to the Common Terminology Criteria for AEs. Patients with incomplete medical records were excluded. Results:  We included 60 patients treated for Crohn’s disease and 22 for ulcerative colitis. Of those, 37 patients were on IFX, 25 patients on ADA, while 20 patients were treated with both medications during different intervals. Median follow-up of an individual patient was 36.5 months (range 1-99). At least one AE was reported for 27 patients (47.4%) on IFX and 16 patients (35.6%) on ADA. The overall number of observed AEs was 67, of which 63 (94.03%) were mild to moderate, and 4 (5.97%) were severe. The most common 1

Volume 37 Number 8S